A large percentage of patients who visit the ophthalmology
practice are within the fertile age range. For this reason, the physician must
have in-depth knowledge of the impact that pregnancy can have on ocular
physiology and previously existing diseases, but must also be fully aware of the
levels of safety of each drug for gestation and breastfeeding. This is the only
way to minimize the secondary effects that treatment of pregnant women can have
on the developing fetus or the newborn.

By way of continuation of the first part of this article, this
second part describes the levels of safety in gestation and breastfeeding for
the drugs most commonly utilized in ophthalmology. The letters A, B, C, D and X
in brackets indicate the safety category of the active principles according to
the FDA.

1. ANTI-INFLAMMATORIES

Anti-inflammatories constitute a heterogeneous group of chemical
substances divided in three main groups: steroid anti-inflammatories
(corticoids), non-steroid anti-inflammatories (NSAID) and immunomodulators.

Such pharmacological abundance allows us to adapt a treatment to
each patient –particularly during gestation– as we have a number of chemical
structures available featuring different properties, indications and of course
degrees of efficacy, tolerance and administration routes.

1.1. Corticoids

On the basis of bioavailability, place of action and intrinsic
potency of the molecule, corticoids used in ophthalmology are classified in
three groups: weak, such as medrisone (not available in Spain as an individual
component), intermediate such as cortisone, hydrocortisone, fluorometholone and
deflazacort, and potent such as prednisone, prednisolone, dexamethasone,
triamcinolone, betamethasone and rimexolone (1). In addition,
medroxyprogesterone is a progestogen with low anti-inflammatory potency but with
anti-collagenase activity (table 1).

Prednisone has been classified by the FDA in category B, while
the remainder of corticoids are in level C because animal studies have
demonstrated adverse effects in the fetus although there are no adequate or
properly controlled studies in pregnant women, or studies on animals have not
been carried out and there are no adequate, well controlled studies on pregnant
women. Said drugs must be administered only if the possible desired benefit
justifies the potential risk for the fetus.

Dexamethasone is compatible with the lactation period. In
contrast, triamcinolone, cortisone, hydrocortisone and deflazacort should be
avoided. As regards the remainder of active principles, the physician must
determine whether or not they are strictly necessary.

Medroxyprogesterone is totally contraindicated during pregnancy
and breastfeeding and is a category X drug.

1.2. Non-steroid anti-inflammatory drugs

According to the FDA, NSAIDs should not be prescribed for
pregnant women. Studies on animals have shown that, when the administered
amounts are large enough to produce negative effects on the mother, the growth
rate and weight of the fetus diminishes (3). The NSAIDs most widely utilized in
Ophthalmology are: diclofenac (B), flurbiprofen (D), indomethacin (D), ketorolac
(C), pranoprofen (B) and ibuprofen (B/D) (Table 2). The latter active principle
should be avoided during the first and second quarter of pregnancy unless
strictly necessary. On the contrary, it is completely contraindicated in the
third quarter as it is related to cardiopulmonary toxicity and kidney
dysfunction in the fetus. In addition, it could expose the mother and the fetus
to extended hemorrhage times, anti-aggregating effects and inhibition of uterus
contractions (2).

To conclude, NSAIDs should be administered only if the expected
desired benefit justifies the dangers for the fetus. Whenever possible, it is
preferable to substitute NSAIDs by paracetamol (B), a safe analgesic during
gestation and compatible with the possibility of breastfeeding. Diclofenac can
be utilized with caution during the lactation period, but the rest are
forbidden.

Cyclosporine A (C) is the most frequently prescribed
immunomodulator drug in ophthalmology. It has not been studied whether it is
excreted in maternal milk after topical administration, although it is known
that when administered through other routes it is eliminated through the milk.
Even though concentrations of cyclosporine A are not detected in blood after
topical administration, it is not advisable to prescribe it during lactation
(5).

Generally, immunomodulating drugs are not convenient during
pregnancy as most have the D level of safety according to the FDA. Specifically,
metotrexate exhibits a teratogenic and abortive risk and it is advised to
utilize contraception methods up to month 6 after the last dose in women and
month 3 in men.

Azathioprin can delay intrauterine growth and produce
mutagenicity or teratogenicity, contraception being proposed in this case as
well. Chlorambucyl develops infertility, increases the risk of leukemia and is
also teratogenic.

Finally, in all biological therapies it is recommended to avoid
pregnancy and lactation up to 6 months after ending the treatment (5).

2. ANTIALLERGICS AND VASOCONSTRICTORS

It is quite common for ophthalmologists to see patients with
allergy symptoms. The ocular discomfort they describe and the difficulties they
experience in their daily activities make it necessary to treat said symptoms
independently of pregnancies.

Vasoconstrictor and antiallergic drugs are prescribed in the
presence of allergic clinic. The former group includes phenylephrine (C),
nafazolin (C), oximethazolin (B) and tetrizolin (C) (table 4).

There are no clinical trials on anti-glaucomatous drugs during
pregnancy. In general it is preferable to suspend medical treatment temporarily
and closely follow-up the patient provided that the progression risk is low (7).

Prostanoids (latanoprost, travoprost, bimatoprost) are
forbidden. Teratogenic effects have been observed in animals and could stimulate
uterine contractions (8). The recently marketed tafluprost does not have
sufficient trials to classify its safety during pregnancy (table 6).

Brimonidine is the only ocular hypotensor with safety category B according to
the FDA. The rest of ·2-adrenergic agonists (apraclonidine and clonidine) are in
level C.

Cholinergic agonists, with pilocarpin as the only
anti-glaucomatous example in the market, are in safety category C.

b

-blockers (timolole maleate, carteolol, levobunolol and
betaxolol) are in level C. Even so and extrapolating the experience with these
drugs via the systemic route, there are numerous studies that support their use,
on the basis of their indication for treating arterial hypertension or
arrhythmia during pregnancy. On the basis of this argument, the European
Glaucoma Society proposed b-blockers as drugs of
first choice for pregnant patients with high progression risk (7).

Carbonic anhydrase inhibitors (acetazolamide, brinzolamide and
dorzolamide) have also been classified by the FDA in category C (table 6).

However, glaucoma specialists recommend avoiding brimonidine
during the latter months of pregnancy due to the possible risk of respiratory
depression in the newborn, as well as b-blockers to
reduce as much as possible the potential risks derived from the systemic effects
of medication in the newborn. Although there is not enough clinical evidence on
these two recommendations, the severity of their consequences call for prudency
in their use and the search for alternatives whenever possible.

The American Pediatric Academy has approved the administration
of b-blockers and carbonic anhydrase inhibitors for
lactating mothers, although with caution. a2-adrenergic
agonists must be avoided as they are contraindicated for the pediatric
population (8).

4. ARTIFICIAL TEARS

The dynamic nature of the lachrymal tear and its complex
composition, with multiple individual variations, render the reproduction of
tears in laboratories practically impossible, making it necessary to develop
tear substitutes. The main component of artificial tears is water with the
addition of an active principle and a range of elements which stabilize the pH
and regulate the tear stability (9). For this reason there are no adverse
effects described after the use of humidifying tear treatment excepting those
derived from allergy to any of the components or preservatives.

There is no references to complications arising from the
prescription of lachrymal substitutes in pregnant and breastfeeding women. Even
so, it is preferable to utilize the products which have the longest experience
as there are no clinical trials for this period of life.

The most common active principles in ocular lubricants are:
carbomere (C), carmelose (C), hypromelose (C), paraffin (C), lanolin (C),
polyvinyl alcohol (C) and povidone (C). There is not enough experience with
hyaluronic acid during gestation and therefore the risk/benefit ratio must be
assessed (table 7).

Carmelose and polyvinyl alcohol have proved to be compatible
with breastfeeding. Hyaluronic acid, carbomere, paraffin and lanolin require
caution in their use, while hypromelose and povidone should be avoided (table
7).

5. ANTIANGIOGENICS

Antiangiogenic drugs constitute a set of highly current active
principles useful in ocular diseases associated to vascular endothelial growth
factor such as choroidal and retinal neovascularization, macular edema,
intraocular inflammatory process and corneal and iridian neovascularization
(10). Some antiangiogenics are approved by the FDA for non-intraocular uses such
as intravitreal bevacizumab or triamcinolone. Due to the fact that these drugs
are used as a compassionate medication, there are no studies accepted by
international bodies supporting their safety and efficacy, even less in
gestating women (11).

While triamcinolone is in category C, bevacizumab is
contraindicated. For the latter there are no data about pregnant women and
animal studies have exhibited reproductive toxicity, including malformations
(table 8). It is known that immunoglobulins G (IgG) traverse the placenta and
are assumed to inhibit angiogenesis in the fetus; therefore IgG are expected to
cause severe birth defects if administered during pregnancy (2).

In contrast, ranibizumab and pegaptanib have been approved by
the FDA for treating age-related macular degeneration of the exudative type,
although they have not been studied in pregnant women. Pegaptanib is in Category
C. As for ranibizumab, although its systemic concentrations are low, it should
be considered as potentially teratogenic and embryo-fetotoxic due to its action
mechanism (2). There are no data about women or studies on animals. It should
not be used in pregnancy unless the benefit exceeds the fetal risk (table 8).

Fluocinolone acetate (C) was accepted by the FDA in 2005 as an
intravitreal device for treating macular edema associated to chronic uveitis. It
is eliminated through maternal milk and therefore, as with the remainder of
antiangiogenics, its use during lactation is not allowed.

6. VITREOUS SUBSTITUTES

Vitreous substitutes are frequently utilized in vitreoretinal
surgery to maintain the ocular anatomy. At present there are perfluorocarbonated
liquids (perfluoro-n-octane, perfluoromethyldecalin, perfluorotributylamine,
perfluorofenantrene), non-expandable intraocular gases (air, xenon), expandable
gases (sulphur hexafluoride, perfluoromethane, perfluoroethane,
perfluoropropane) and intraocular silicone (polydimethylsilicone, fluorosilicone
and heavy silicones) (12). There is no record of clinical data about pregnant or
lactating women and accordingly these substitutes should be avoided in both
cases, or at least should be utilized with caution (table 9).

7. BIOADHESIVES

Currently available bioadhesives are cyanoacrylates, acrylic
polymers and biological adhesives. The latter are made up of fibrinogen,
thrombin and calcium (13). As in the previous pharmacological group, there is no
experience during pregnancy or lactation (table 10).

8. BOTULIN TOXIN

The active principle is an exotoxin synthesized by
Clostridium botulinum, a grampositive sporulated anaerobic bacteria. This
toxin is able to develop a reversible flaccid muscular paralysis (14).

There are 2 serotypes; serotype A exhibits a safety level of C
whereas serotype B involves unknown potential risks for humans, making its use
unadvisable for pregnant patients unless strictly necessary (2). Both serotypes
are macromolecules which, under normal conditions, would not pass through the
blood-brain barrier or the placenta but, due to the absence of experience in
pregnant and lactating women, its use is not advisable (table 11).

9. VISCOELASTICS

Viscoelastics are necessary in multiple ophthalmological
surgical procedures and contain one or more of the following substances in
various concentrations: sodium hyaluronate, chondroitin sulphate and
hydroxypropylmethylcellulose (14). At this time there is no research on the use
of viscoelastics in pregnant or lactating women and therefore its utilization is
not recommended (table 12).

10. VITAMIN SUPPLEMENTS

At present there are a number of vitamin complexes in the market
which, as a supplement to our food intake, constitute a balanced supply of
nutrients and antioxidants. Supplements also increase the defense mechanisms of
the body against oxidative processes which are a potential hazard for the visual
function, as is the case of ultraviolet radiation.

Vitamin supplements have multiple functions, as many as
components included in their formulation. Accordingly, carotenoids are pigments
located in the macula with antioxidant properties and which also protect
photoreceptors. Vitamins A, C and E normalize numerous metabolic reactions,
delaying the ageing process activated by free radicals. Vitamin group B is
necessary for the proper function of the nervous system and eyes because it
provides the body the energy it needs for carrying out adequately various
metabolic reactions. In turn, minerals are part of the cell antioxidant system,
and finally fatty acids are essential for the retina (2).

With the exception of tocopherol, which exhibits a C fixed
safety level, the rest of vitamins have different safety ratings according to
the dosage being administered. Specifically, vitamin A can reach category X when
exceeding the recommended dosage (table 13). For this reason and considering the
absence of sufficient studies on pregnant patients, it is advised to obtain said
active principles through healthy and well-balanced food intake during pregnancy
and lactation, administering vitamin supplements only in extreme cases (2).